To provide an efficacious dose of a therapeutic agent at the site of treatment, systemic administration of the therapeutic can often lead to adverse or toxic side effects to the patient. Local delivery provides smaller total amounts of the therapeutic minimizing adverse side effects and targets the therapeutic to the site of treatment. One way to locally deliver a therapeutic agent to a treatment site is to coat the therapeutic agent onto the surface of an implantable medical device.
Many matrix systems have been developed to deliver a bioactive molecule to a substrate, such as the surface of a medical device. Typically, the bioactive molecule is covalently coupled to the substrate, or more commonly, the substrate is coated with a matrix containing bioactive molecule. The matrix may be composed of a polymer into which is trapped the bioactive molecule, and as the matrix degrades, released is the bioactive molecule. Thus, the efficiency of release of the bioactive molecule from the polymer matrix depends on individual matrix characteristics such as the affinity of the matrix for the bioactive molecule; and the matrix degradation rate, density, and pore size. Typically, materials used in such matrix systems include polymers such as polylactides, polyglycolides, polyanhydrides, polyorthoesters, polylactic and polyglycolic acid copolymers, alginate, poly(ethylene glycol), polyoxyethylene oxide, carboxyvinyl polymer, and poly(vinyl alcohol). Natural matrix proteins/polymers used to encapsulate entrap bioactive molecules for release include collagen, glycosaminoglycans, and hyaluronic acid, which are enzymatically digested in the body.
Recently described are biological coating compositions for medical devices (see, e.g., published patent applications US 20060051395, US 20070160644, co-pending and commonly owned) comprising a biofunctional composition. The biofunctional composition comprises a peptide having binding specificity for a surface material comprising the surface onto which is to be applied the coating composition, and a peptide having binding specificity for a therapeutic agent; wherein covalently coupled are the peptide having binding specificity for a surface material and the peptide having binding specificity for a therapeutic agent. The coating composition may further comprise therapeutic agent non-covalently bound to peptide having binding specificity for the therapeutic agent. Peptide-based biomaterials have gained interest as novel materials for biomedical applications (see Fairman R. Akerfeldt K S. Curr Opin Struct Biol 2005; 15 (4): 453-63 and Rajagopal K, Schneider J P. Curr Opin Struct Biol 2004; 14 (4): 480-6). A large variety of synthetic advantages of peptide-based biomaterials include their programmability, biodegradability, and bioresorbability. In addition, peptides can be isolated that bind to specific therapeutic agents or the surface of biomaterials (Grinstaff et al. U.S. Patent Application 20060263830; Beyer et al. U.S. Patent Application 20060051395).
Certain peptides are able to self assemble into gel like membranes when incubated in the presence of low concentrations of monovalent cations (U.S. Pat. Nos. 5,670,483; 6,548,630) or based on the spatial matching of the complementary functional groups (U.S. Pat. No. 7,399,831). Versatile side-chain functional groups and non-covalent interactions of 20 amino acids enable one to design peptides for numerous applications. Most designed peptide-based biomaterials are amphipathic, with both hydrophilic and hydrophobic amino acids in their sequence. The order and repeat of these amino acids in the primary sequence determines the nature of the secondary structure adopted by these peptides and, thereby, the final morphology of the assembled biomaterials. Assembly of these peptides is driven by the non-covalent interactions between the side-chain functional groups and backbone amides, which mostly involve hydrophobic, electrostatic, hydrogen bonding, and π-stacking interactions (Ramachandran, S. Yu, Y. B. Biodrugs 2006; 20 (5): 263-269). Designed proteins offer favorable properties such as precision and tight regulation of self assembly by using environmental cues such as pH, ionic strength and temperature (Whitesides, et al. (1991) Science 254, 1312-1319; Yeates, T. O. & Padilla, J. E. (2002) Curr. Opin. Struct. Biol. 12, 464-470; MacPhee, C. E., Woolfson, D. N. (2004) Curr. Opin. Solid State Mater. 8, 141-149).
Nature forms complex multicomponent three-dimensional structures through spontaneous association of molecules termed “molecular self-assembly” (Whitesides, et al. (1991) Science 254, 1312-1319). The self-assembly process is mediated through weak intermolecular bonds, such as van der waals bonds, electrostatic interactions, hydrogen bonds and stacking interactions. These relatively low energy interactions are combined together to form intact and well-ordered supramolecular structures. The self-assembly of peptide amphiphiles into nanostructures creates a dense hydrocarbon-like microenvironment within an aqueous gel. The environment created locally upon assembly makes peptide amphiphile nanostructures and other self-assembling systems potentially ideal candidates for the delivery of hydrophobic or water-insoluble molecules in vivo (Guler, et al. J Mater Chem 2005,15, 4507-4512). In addition, peptide sequences that bind to cells or other biologics can be attached to self-assembling peptides to generate peptide nanofibers that bind biologics (U.S. Pat. No. 7,399,831; U.S. Patent Application 20050272662; U.S. Patent Application 20050209145).
Within the art, however, there still exists a need to generate self-assembling peptides that both bind a therapeutic agent and to the surface of a medical device. These dual functional, self-assembling peptides could be used for controlled, local deliver of a therapeutic agent from an implanted medical device.